Cycloalkyl-diamines for the treatment of pain

ABSTRACT

The invention is directed to a method of treatment for pain, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

This patent application claims the benefit of U.S. Provisional Application Ser. No. 62/889,801, filed Aug. 21, 2019.

BACKGROUND OF THE INVENTION

This invention is directed to a method of use for the treatment of pain in a mammal, comprising the administration of a therapeutically effective amount of a compound of formula I, of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pain has been defined as an unpleasant feeling often associated with a physical injury or illness, but in medical terms pain is typically regarded as a symptom of an abnormal, underlying condition. The duration of pain may be acute or chronic, and it may have subtle or disabling effects on patients. The causes of pain are also many and varied, arising from external (i.e., traumatic injury) or internal (e.g., surgical pain, diabetes, cancer) causes. Many patients obtain some relief using currently available medications, whether over-the-counter (OTC) or prescription. Yet despite all the options, there is still a segment of the population who remain permanently disabled by their pain. Even the most effective narcotic medications available may not reduce the pain to tolerable levels and, in fact, may often induce severe side effects that must also be managed carefully.

Clinically, pain is associated with a variety of diseases and disorders including cancer, traumatic nerve damage, diabetic neuropathy and spinal cord injury, which are generally perceived by patients to be chronic and debilitating. The International Association for the Study of Pain (IASP) recently organized a task force of experts to define chronic pain for a recent issue of the World Health Organization's International Classification of Diseases (ICD) (see R-D Treede, et al, “A Classification of Chronic Pain for ICD-11” (2015); Pain, 156(6):1003-1007). The major categories in the new classification include chronic pain from cancer, post-traumatic nerve damage, diabetic neuropathy, chronic primary pain, fibromyalgia, post-surgical pain, chronic visceral pain and musculoskeletal pain.

Whereas moderate pain is often treated with analgesics (for neuropathic pain) or anti-inflammatory drugs (for inflammation induced pain, e.g., in arthritis), morphine and related opiate analgesics are the most effective and, therefore the most widely prescribed drugs for the treatment of chronic, severe pain. However, opiates are frequently overprescribed and potentially dangerous when misused or abused by patients, leading to dependency. They may also be associated with side effects including dysphoria, sedation, gastrointestinal disturbances and death.

Opioid receptors are found in the Central Nervous System (CNS) of mammals, particularly humans, and are included in the broader class of G-Protein Coupled Receptors (GPCRs). They have been characterized, based on their functional reactivity to specific agonists and antagonists, as delta (δ), kappa (κ) and mu (μ) subtypes. These opioid receptors are highly distributed in the CNS in areas associated with pain, including the cerebral cortex, amygdala, hypothalamus and spinal cord.

Kappa Opioid Receptors (KOR) are also expressed in the peripheral nervous system and activation of these receptors by selective agonists has been shown to produce a reduction of pain and inflammation in animal studies designed to model human pain (TW Vanderah, (2010) Clinical Journal of Pain, 26:S10-S15), (F Simonin, et al, (1998) EMBO Journal, 17:886-897).

However, activation of central KORs may also be associated with significant dysphoria, which can promote addiction in patients, as well as heightened anxiety and restless behavior. It is predicted that selective KOR agonists that do not cross the blood-brain-barrier (BBB) could provide a significant advantage in the treatment of severe pain without the associated CNS effects observed with some potent opiate analgesics currently in use. KOR activation by specific agonists such as the highly selective KOR agonist Salvinorin A have produced “spaciotemporal dislocation rather than hallucinatory behavior that is frequently dysphoric” (Y Feng, B L Roth (2004) Life Sciences 75:2615-2619).

Of particular interest to MediSynergics, LLC (MS) as a drug research company is the discovery of new, safe therapies for reducing pain, particularly in light of the increasing number of deaths in the US from the opioid crises and the misuse of potent analgesics like oxycodone. Narcotic medications are designed to regulate opioid receptors in the body, but their abuse is of particular concern because long-term misuse has been associated with and increasing prevalence of addiction and other side effects (e.g., respiratory, constipation) that can severely impact quality of life for patients.

Recently, there has been increased awareness of the potential for compounds which function as Sigma-1 receptor ligands. The structure and functions of this “receptor”, which structurally and functionally appears to be a “chaperone protein”, have been described in a variety of publications (e.g., G Duncan L Wang, (2005) Experimental Eye Research, 81:121-122; J L Ortega-Roldan, F Ossa, J R Schnell (2013) Journal of Biological Chemistry, 288(29): 21448-21457: FP Monnet (2005) Biology of the Cell, 97:873-883 (doi:10.1042/BC20040149); Ishikawa M, Hashimoto K (2010) Journal of Receptor, Ligand and Channel Research, 3:25-36).

A small but growing number of drug researchers have proposed the Sigma-1 (61) receptor subtype as a unique, prime target for treating such diverse human disorders as pain, Alzheimer's disease, Parkinson's disease, stroke and cancer. Studies with laboratory animals and human trials (e.g., using Esteve's E52862) have confirmed that some of these investigational drugs are capable of significantly reducing such diverse pain conditions as diabetic neuropathy, chemotherapy-induce neuropathy in cancer patients and neuropathy following spinal cord injury to manageable levels. There is little evidence reported of serious abuse potential with these compounds.

More recently, the Sigma-2 (σ2) receptor has also been identified and characterized (J Sahn, G L Meija, P R Ray, S P Martin, T J Price, “Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice” ACH Chem Neurosci (2017) 8(8): 1801-1811). Compounds with Sigma-2 activity are also reported to be potentially useful for neuropsychiatric disorders (e.g., schizophrenia) and a variety of cancers (“Sigma-2 Receptor”; URL: https://en.wikipedia.org/wiki/Sigma-2_receptor).

Specifically, compounds which function as antagonists of the Sigma-1 receptor are of particular interest. S. Castany, et al, have studied the effects of MR309 on reduction of neuropathic pain following spinal cord injury in mice (S Castany, G Gris, J Vela et al, www.nature.com, “critical role of sigma-1 receptors in central neuropathic pain-related behaviors after mild spinal cord injury in mice” Scientific Reports (2018), 8:3873; doi:10.1038/s41598-018-22217-9). N Paniagua, et al, have also reported on the successful blockade by E-52862 of Sigma-1 receptors, resulting in reversal of neuropathic and vascular signs in a ZDF rat model (N Paniagua, R Giron, G Goicoechea, et al, “Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats”, European Journal of Pain (2017), 21:61-72). Clinically, J Bruna, et al, have recently reported the results from human studies using MR309 to moderate Oxaliplatin-induced neuropathy in patients with colorectal cancer (J Bruna, S Videla, A Argyriou, et al, “Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial”. Neuropathy (2018) 15-178-189). Extensive reviews of the use of Sigma-1 antagonists have also recently been published (J Vela, M Merlos, C Almensa “Investigational sigma-1 receptor antagonist for the treatment of pain”, Expert Opinion Investigational Drugs (2015) 24(7):883-896: D Zamanillo, L Romera, et al, “Sigma 1 receptor: A new therapeutic target for pain” European Journal of Pharmacology (2013) 78-93.

The market opportunities for discovery of a well-tolerated, effective and non-addictive treatment for pain are tremendous. Purdue Pharma's OxyContin sales grew from $48M US in 1996 to nearly $1.1B US in 2000 as a result of very aggressive marketing. By 2004, it had become one of the leading drugs of abuse in the US. A recent report (MarketWatch, January 2019) evaluating the global pain market predicted a compound annual growth rate (CAGR) for pain therapy of 3.4% —to $85.5B US by 2026. Major players in this sector include large pharma (Pfizer, J&J and Lilly) as well as smaller biopharma companies including Teva and Mylan. The report further cites estimates of up to 100 million patients in the US alone who suffer from chronic pain. With an increasing prevalence of some diseases, especially cancer, the market is expected to continue to expand. New approaches to pain management beyond opiate chemotherapy are expected to compete with currently available medications, especially if they demonstrate reduced addictive, abuse and overdose liabilities.

A breakthrough treatment for chronic pain, with minimal or no addictive liabilities could garner a huge market. Many patients in this cohort are incapable of contributing fully to the economy in terms of useful employment. They often become burdens to the medical community and their families with respect to medical care. The loss of life due to addiction and abuse of opiate treatments is incalculable. Reducing these liabilities could help to get such needed medications to those who truly need them.

The present invention relates to the use of novel cycloalkyl-diamines of structural formula I and to their pharmaceutical compositions in the treatment of pain disorders. Many of the compounds disclosed in this application exhibit significant affinity as Sigma-1 ligands.

MediSynergics, LLC has previously disclosed the use of cycloalkyl-diamines (i.e., derivatives of ketamine) for a variety of human and animal disorders. These include parasitic diseases such as trypanosomiasis (“Cycloalkyl Diamines; U.S. Pat. No. 9,126,891, issued Sep. 8, 2015), psychiatric disorders such as depression and schizophrenia (“Cycloalkyl-diamines for CNS Disorders”, U.S. Pat. No. 9,283,196, issued Mar. 15, 2016), cancer (“Anti-cancer Cycloalkyl Diamines”, U.S. Pat. No. 9,345,673, issued May 24, 2016) and amyotrophic lateral sclerosis, or ALS (“Cycloalky-diamines for Neurodegenerative Disorders”, U.S. Pat. No. 9,381,170, issued Jul. 5, 2016).

SUMMARY OF THE INVENTION

The present invention is directed to a method for the treatment of pain in a mammal, including a human, by administering a compound of the formula I, or a pharmaceutically effective salt(s) thereof, in an amount which is effective at reducing or eliminating pain in said mammal, wherein:

X and Y are independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, CF₃, C₂F₅, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₃-alkoxy, aryl, heteroaryl, —(C═O)—R5, NH—(C═O)—R5, —NR5-(C═O)—R6, —(C═O)—NHR5 and (C═O)—NR5R6;

R1 is hydrogen:

R2 is hydrogen or C₁-C₆-alkyl:

R3 is hydrogen or C₁-C₆-alkyl:

R4 is selected from the group consisting of C₁-C₆-alkyl, C₃-C₇-cycloalkyl, (CH₂)_(n)—R7, or

NR3N4 is a 5- to 12-membered cyclic or bicyclic ring system containing up to two additional heteroatoms in the rings selected from N, O and S;

R5 is selected from C₁-C₆-alkyl and aryl;

R6 is selected from C₁-C₆-alkyl and aryl; or NR5R6 is a 5- to 12-membered cyclic or bicyclic ring system containing up to two additional heteroatoms in the ring, selected from N, O and S;

R7 is independently selected from the group consisting of H, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, (C₁-C₆-alkoxy)-, (C₁-C₆-alkoxy)-(C₁-C₆-alkyl), NR8R9, NR8R9-(C₁-C₆-alkyl), aryl, heterocyclyl and heteroaryl;

R8 and R9 are independently selected from hydrogen, C₁-C₆-alkyl and aryl, or taken together with the N atom to which they are attached form a 3- to 8-membered ring containing up to two additional heteroatoms, selected from N, O and S;

N is an integer between 1 and 6, and

“a” and “b” denote chiral carbon centers.

Preferred embodiments of the present invention include the compounds of formula I in which:

(A) R2 is methyl, R1 and R3 are hydrogen, y is hydrogen:

-   -   X is halogen;     -   N is an integer between 0 and 6; and     -   R7 is aryl or heteroaryl.

(B) R2 is methyl, R1 and R3 are hydrogen; Y is hydrogen;

-   -   X is halogen;     -   N is an integer between 0 and 6; and R7 is heterocyclyl.

(C) R2 is methyl, R1 and R3 are hydrogen; Y is hydrogen;

-   -   X is halogen;     -   N is an integer between 0 and 6; and     -   R7 is NR8R9.

Preferred compounds of formula I in accordance with the present invention include:

-   Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine     trihydrochloride; -   Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine     trihydrochloride; -   Cis-(1S,2S)-1-(2-chlorophenyl)-N²-[3-(4-fluorophenyl)propyl]-N¹-methyl-cyclohexane-1,2-diamine     dihydrochloride; -   Trans-(1S,2R)-1-(2-chlorophenyl)-N²-[3-(4-fluorophenyl)propyl]-N¹-methyl-cyclohexane-1,2-diamine     dihydrochloride; -   Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-phenylpropyl)cyclohexane-1,2-diamine     dihydrochloride; -   Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-phenylpropyl)cyclohexane-1,2-diamine     dihydrochloride; -   Cis-(1S,2S)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl)-N¹-methyl-cyclohexane-1,2-diamine     dihydrochloride; -   Trans-(1S,2R)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl)-N¹-methyl-cyclohexane-1,2-diamine     dihydrochloride; -   Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclo-hexane-1,2-triamine     dihydrochloride; -   Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclo-hexane-1,2-triamine     dihydrochloride; -   Cis-(1R,2S)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine     dihydrochloride; -   Trans-(1R,2R)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine     dihydrochloride; -   Cis-(1S,2R)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine     dihydrochloride; -   Trans-(1S,2S)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine     dihydrochloride; -   Cis-(1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine     trihydrochloride; -   Trans-(1R,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine     trihydrochloride; -   Cis-(1R,2S)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl)-N¹-methyl-cyclohexane-1,2-diamine     dihydrochloride; -   Trans-(1R,2R)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl)-N¹-methyl-cyclohexane-1,2-diamine     dihydrochloride; -   Cis-(1S,2S)-1-(2-chlorophenyl)-N²-(3,4-dichlorobenzyl)-N¹-methylcyclo-hexane-1,2-diamine     dihydrochloride; -   Trans-(1S,2R)-1-(2-chlorophenyl)-N²-(3,4-dichlorobenzyl)-N¹-methylcyclo-hexane-1,2-diamine     dihydrochloride; -   Cis-(1S,2S)—N²-(3-aminopropyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine     trihydrochloride; -   Trans-(1S,2R)—N²-(3-aminopropyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine     trihydrochloride; -   (1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)-cyclohexane-1,2-diamine     tetrahydrochloride; and -   (1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)-cyclohexane-1,2-diamine     tetrahydrochloride. -   Other compounds of the invention will include, but are not limited     to: -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidin-1-yl)propyl)cyclo-hexane-1,2-diamine: -   (1R,2S)—N²-(3-(1H-pyrrol-1-yl)propyl)-1-(2-chlorophenyl)-N¹-methylcyclo-hexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(2-methyl-1H-imidazol-1-yl)-propyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidine-1-yl)propyl)-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(3-(dimethylamino(propyl)-N¹-methyl-cyclohexane-1,2-diamine; -   (1R,2S)—N²-(1-chlorobenzyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-(2-chlorophenyl)-N²-(3,5-difluorobenzyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(4-(trifluoromethyl)benzyl)-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(4-((trifluoromethyl)thio)benzyl)-cyclohexane-1,2-diamine; -   (1R,2S)—N²-(5-chloro-2-fluorobenzyl)-1-(2-chlorophenyl)-N¹-methylcyclo-hexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(5-methoxy-2-methylbenzyl)-N¹-methyl-cyclohexane-1,2-diamine: -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(thiazol-2-ylmethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(thiophen-3-ylmethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(furan-2-ylmethyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(thiophen-2-ylmethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-((methyl-1H-pyrazol-4-yl)methyl)-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(cyclobutylmethyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(cyclopropylmethyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-neopentylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(2,2-difluoroethyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²-(cyclopropylethyl)-N¹-methylcycohexane-1,2-diamine: -   (1R,2S)-1-(2-chlorophenyl)-N²-cyclohexylmethyl)-N¹-methylcyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-quinuclidin-3-yl)cyclohexane-1,2-diamine: -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-quinuclidin-3-yl)cyclohexane-1,2-diamine: -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyridine-4-ylmethyl)cyclohexane-1,2-diamine: -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyridine-2-ylmethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyrimidin-2-ylmethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-methylpyridin-4-yl)methyl)-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyrazin-2-ylmethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(quinoline-6-ylmethyl-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-((1-methyl-1H-indol-5-yl)methyl)-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²—((S)-1-(4-methoxyphenyl)ethyl)-N¹-methyl-cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N²—((R)-1-(4-methoxyphenyl)ethyl)-N¹-methyl-cyclohexaane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-1-phenylethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-1-phenylethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-1-(p-tolyl)ethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-1-(p-tolyl)ethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-2-phenylpropyl)cyclohexane-1,2-diamine: -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-2-phenylpropyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-1-(p-tolyl)ethyl)cyclohexane-1,2-diamine; -   (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-1-(p-tolyl)ethyl)cyclohexane-1,2-diamine; -   (R)-1-((1S,2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexyl)-N,N-dimethyl-pyrrolidin-3-amine;     and -   (S)-1-((1S,2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexyl)-N,N-dimethyl-pyrrolidin-3-amine.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I may be prepared as described in the following reaction schemes and discussions. Unless otherwise indicated, X, Y, R1, R2, R3, R4, R5, R6, R7 and structural formulae II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV in the reaction schemes and discussion that follow are defined as above.

According to Scheme 1, a ketone of the general formula II, wherein X, Y, R1 and R2 are as previously defined, may be converted directly into the corresponding compound of the formula I, via an intermediate of the general formula IV, by reacting it with one or more equivalents of a primary amine of the general formula III in the presence of a reducing reagent. Reducing reagents that may be used include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium aluminum hydride, hydrogen gas and a metal catalyst, or zinc plus hydrochloric acid. This reaction is typically conducted in a reaction inert solvent at a temperature from about 0° C. to about 150° C., but may be conducted in the absence of solvent. Suitable reaction inert solvents include lower alcohols (e.g., methanol, ethanol, isopropanol), 1,2-dichloroethane, acetic acid or tetrahydrofuran. Preferably the reaction is conducted with an excess of the corresponding amine III, in the absence of additional solvent, at a temperature of about 110° C. and using the reducing agent sodium cyanoborohydride.

Alternatively, the reaction of a compound of formula II with an amine compound of the formula III may be carried out in the presence of a dehydrating agent (e.g., titanium tetrachloride) or by using an apparatus designed to azeotropically remove the water generated, to produce an imine of the formula IV. This imine may then be converted to the title product of formula I by reduction of the C═N double bond with a reducing agent as described above, preferably with sodium cyanoborohydride in the presence or absence of a suitable, reaction inert solvent as described in the preceding paragraph at a temperature of about 0° C. to about 150° C. and preferably at about 110° C. Other suitable dehydrating agent/solvent systems include titanium tetrachloride in dichloromethane, titanium isopropoxide in dichloromethane and activated molecular sieves in toluene or in dichloromethane.

When a secondary amine of the general formula V (i.e., HR3R4) is used, an alternative method involves the formation of an enamine of the general formula VI, which can be reduced to the title product of formula I through the use of a selective reducing agent or selective reduction conditions known to one familiar with the art of organic synthesis. Using this procedure, as shown in Scheme 2 above, the intermediate enamine VI may be isolated and purified, if it is stable, or it may be used directly in the reduction step to generate a diamine of general formula I. Selective reducing agents and reagents 1.0 to facilitate the conversion of intermediate VI to the compounds of formula I include: formic acid, hydrogen gas and a metal catalyst (e.g., Pd metal on carbon, Pt metal on carbon).

In another method (Scheme 3, below) for the preparation of the compounds of the present invention, an intermediate oxime (VII) can be prepared through the reaction of the starting ketone I and hydroxylamine. Synthesis of such oximes is well precedented in the chemical literature (e.g., see J L LaMattina, et al, Synthesis (1980) 329-330). It is also known that intermediate oximes like VII are capable of forming two different isomers, denoted as Z- and E-oximes. These isomers may or may not react differently in the subsequent conversion to intermediates of general formula VIII (i.e., I, where R3, R4=H), and one of the oxime isomers may be less reactive or resistant to reduction to intermediate VIII. The reduction to VIII can be achieved using one of a variety of reagents and procedures, including Zn-Acetic acid, Na metal and ethanol, BH₃, and NaBH₃CN—TiCl₃.

In the next step, compound VIII can be converted to a compound of general formula X by subjecting it to a reductive amination with an aldehyde of general formula IX (for examples, see Jerry March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4^(th) Ed., John Wiley & Sons, New York, N.Y. (1992), pp 898-900) followed by alkylation of the nitrogen atom of the intermediate of general formula X with a reagent of general formula R9-L, wherein L is a leaving group (e.g., Cl, Br, mesylate) and R9 is C₁-C₃-alkyl. Procedures for these reactions are readily available in the chemical literature and familiar to chemists with skill in the art of organic synthesis.

The starting ketone for the above processes, compound II, may be obtained from commercial sources or may be synthesized as described in the chemical literature (Scheme 4). Such compounds may exist as racemic mixtures or as the individual (+)- and (−)-isomers. Ketamine (II, R1=CH₃, X=2-Cl, R2, Y=H) may be purchased from commercial sources as a mixture of R- and S-isomers. The S-isomer (i.e., esketamine) can also be obtained commercially, but the R-isomer is prohibitively expensive. The individual isomers are reportedly obtained through a resolution process (YA Tawar, et al, “Process for Preparation of Substantially Optically Pure (R)- and (S)-Enantiomers of Ketamine and Its Pharmaceutical Acceptable Salts” (2017), Parapex-Indian Journal of Research, 6(1): 201-204. A modified process, with much improved yields and purity of the individual (R)- and (S)-enantiomers, is detailed in the experimental section that follows.

In general, 1-bromo-cyclopentane is converted to a Grignard reagent (XI) by reaction with magnesium metal in an inert solvent, typically in an ether like diethyl ether or tetrahydrofuran (THF). The Grignard reagent so formed is then reacted with an appropriately substituted aryl-nitrile (XII) in an inert solvent such as hexane, and stirred at room temperature until the reaction is determined to have been completed. The product, an aryl-ketone (XIII), dissolved in a suitable solvent (e.g., chloroform) is then treated with one equivalent of bromine (Br₂), and the resulting α-bromo-ketone (XIV) is isolated by filtration. Compound XIV is then added to a primary amine of general formula R2-NH₂ in an inert solvent (e.g., toluene) and the mixture is heated to reflux. The solvents are subsequently removed under vacuum to obtain the crude α-hydroxy-imine (XV). This intermediate is then heated, typically in a high-boiling solvent like decalin, wherein the compound undergoes a thermal rearrangement to produce the α-amino-ketone (II).

Specifically, the compound II in which X is 2-chloro, Y is hydrogen, R1 is hydrogen and R2 is methyl is commonly referred to as ketamine. It is a Central Nervous System (CNS) active drug that may interact with NMDA (i.e., N-methyl-D-Aspartate) receptors in the brain and has been associated with a variety of behavioral disorders in human and animal studies. The synthesis and utility of ketamine and related analogs as NMDA receptor modulators and disease treatments are described b T. G. Gant, S. Sarshar, et al in US Patent Application 2008/109958 (Apr. 25, 2008).

The compounds of the present invention may have optical centers denoted as “a” and “b” in the preceding schemes and therefore may occur in different enantiomeric configurations. Formula I, as depicted above, includes all enantiomers, diastereomers and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate(s).

Where cis- and trans-isomers are possible (i.e., at positions “a” and “b” in structural formula I) for an embodiment of the inventive compounds of formula I, both cis- and trans-isomers (i.e., diastereomers) are within the scope of this invention.

The present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹³N, ¹⁵N, ¹⁸O, ³⁵S, ³¹P, ¹⁸F and ³⁷Cl, respectively.

Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds, or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example, those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increases in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labeled reagent.

The term “alkyl” refers to straight or branched chains of carbon atoms. Exemplary alkyl groups are C₃-C₁₀ alkyl groups which may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl and the like, including all regioisomeric forms thereof, and straight and branched chain forms thereof. The term “alkyl” is also used to denote straight or branched chains of carbon atoms having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl and the like, as well as straight and branched chains of carbon atoms having one or more carbon-carbon triple bonds, such as ethynyl, propargyl, butynyl and the like.

The term “aryl” denotes a cyclic, aromatic hydrocarbon. Examples include phenyl, naphthyl, anthracenyl, phenanthracenyl. Such aryl groups may further be substituted at available positions with H, F, Cl, Br, I, CN, OH, alkoxy, NO₂, NH₂, NH-alkyl or N,N-dialkyl.

The terms “alkoxy” and “aryloxy” denote “O-alkyl” and “O-aryl”, respectively. The term “cycloalkyl” denotes a cyclic group of carbon atoms, where the ring formed by the carbon atoms may be saturated or may comprise one or more carbon double bonds in the ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, as well as cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. As used herein, the term “cycloalkyl” is also intended to denote a cyclic group comprising at least two fused rings such as adamantyl, decahyronaphthalinyl, norbornanyl, where the cyclic group may have one or more carbon-carbon double bonds in one or more rings, such as in bicyclo(4.3.0)nona-3,6(1)-dienyl, dicyclopentadienyl, 1,2,3,4-tetrahydro-naphthalinyl (i.e., tetralinyl), indenyl and the like.

The term “halogen” represents chloro, fluoro, bromo and iodo.

The term “heteroaryl” denotes a monocyclic or bicyclic aromatic group wherein one or more carbon atoms are replaced with heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Preferred heteroaryl groups are five- to fourteen-member rings that contain from one to three heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of preferred heteroaryl groups include, but are not limited to benzo[b]thienyl, chromenyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthylidinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, triazolyl and tetrazolyl, and said heteroaryl groups may be further substituted as described above in the definition of aryl.

A “unit dosage form” as used herein is any form that contains a unit dose of the compound I. A unit dosage form may be, for example, in the form of a tablet or a capsule. The unit dosage form may also be in a liquid form, such as a solution or suspension.

The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflations.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia). Non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispensing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insulator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the active compounds of the invention for oral, parental or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg/kg to about 100 mg/kg of the active ingredient per unit dose which could be administered, for example, one to four times per day. Toxicity concerns at the higher level may restrict intravenous (i.v.) dosage to a lower level, such as up to 10 mg/kg. A dose of about 0.1 mg/kg to about 100 mg/kg may be employed for oral (p.o.) administration. Typically, a dosage from about 0.1 mg/kg to about 10 mg/kg may be employed for intramuscular (i.m.) injection. Preferred dosages are in the 1.0 mg/kg to about 100 mg/kg range, and, more preferably in the 5 mg/kg to about 50 mg/kg range for i.v. or p.o. administration. The duration of the treatment is usually once per day for a period of one day to three weeks, or until the condition is essentially brought under control.

Aerosol formulation for treatment of the conditions referred to above in the average human are preferably arranged such that each metered dose or “puff” of aerosol contains 0.1 micrograms to 100 micrograms of the active compound of the invention. The overall daily dose with an aerosol will be within the range of 0.1 mg/kg to about 100 mg/kg, and preferably in the range of 1.0 mg/kg to about 25 mg/kg. Administration may be several times daily, for example two, three, four or eight times, giving for example one, two or three doses each time.

As an example, the mammal in need of treatment or prevention may be a human. As another example, the mammal in need of treatment or prevention may be a mammal other than a human.

A compound of formula I which is basic in nature is capable of forming a wide variety of different salts with various inorganic and organic acids. The acid addition salts are readily prepared by treating the base compounds with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acid salts of the active compound used in formulating the pharmaceutical composition of this invention that are basic in nature are those which form non-toxic acid addition salts, e.g., salts containing pharmaceutically acceptable anions. Non-limiting examples of the salts include the acetate, benzoate, beta-hyroxybutyrate, bisulfate, bisulfite, bromide, butyne-1,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogen phosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, monohydrogen phosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, acid phosphate, acid citrate, bitartrate, succinate, gluconate, saccharate, nitrate, methanesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate) salts.

Also included within the scope of this invention are solvates and hydrates of compounds of formula I and their pharmaceutically acceptable salts. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

In the examples that follow, the abbreviations used in this document are intended to have the following, general meaning:

bm: broad multiplet (NMR)

bs; broad singlet (NMR)

d: doublet (NMR

dd: doublet of doublets (NMR)

d.e. diatomaceous earth, a filtering agent

calc.: calculated value

J: coupling constant (NMR)

LC: liquid chromatography

m: multiplet (NMR)

min: minute(s)

m/z: mass to charge ratio (mass spectroscopy)

obsd: observed value

Rf: retention factor or ratio

RT: retention time

RT: room temperature (typically 25° C.)

s: singlet (NMR)

t: triplet (NMR)

T: temperature

tic: thin layer chromatography

Solvents were purchased and used without purification. Yields were calculated for material judged to be homogeneous by thin layer chromatography and NMR.

Thin-layer chromatography was performed on Kieselgel plates eluting with the indicated solvents, visualized by using a 254 nm UV lamp, and stained with an iodo-platinate spray solution (Sigma Aldrich Chemical Co.).

Preparatory chromatography was performed on Analtech Preparative Uniplates (20×20 cm, 2000 mm thick, UV, Silica G) purchased from ColeParmer, Vernon Hills, Ill. 60061, eluting with the indicated solvents and visualized by using a 2554 nm UV lamp.

Liquid chromatography was performed using a Teledyne-Isco CombiFlash Rf+ Lumen instrument with RediSep Rf High Performance Gold 12-, 24-, or 40-gram, 40-60 micron silica gel, disposable flash columns (Teledyne Instruments, Chicago, Ill. and Teledyne ISCO, Lincoln, Nebr.

Nuclear Magnetic Resonance (NMR) spectra were acquired on either a 400 MHz or an 800 MHz Varian NMR Spectrometer (Varian Inc., Palo Alto, Calif.). Chemical shifts for hydrogen, carbon and nitrogen (i.e., ¹H, ¹³C, ¹⁵N) NMR spectra are reported in parts per million (ppm) relative to the singlet for CDCl₃ at 7.23 ppm.

Mass Spectrometry data were obtained on an Advion Expressions CMS (Advion Inc., Ithaca, N.Y. 14850) in the mass range of 100-800 Daltons.

Example 1 Resolution of Racemic (R,S)-Ketamine

Step 1: Preparation of the L-DPPTA Salts of S-(+)-Ketamine and R-(−)-Ketamine.

A 50 mL round-bottom flask fitted with a water condenser and magnetic stir bar was charged with 2.8503 g (12.0 mmol) of racemic ketamine free base (isolated from the hydrochloride salt purchased from Spectrum Chemical Mfg. Corp., Los Angeles, Calif.). Absolute ethanol (14.0 mL, Sigma-Aldrich, Inc., St. Louis, Mo.) was added and the stirred slurry was treated with (−)-di-p-toluoyl-L-tartaric acid (L-DPPTA, 4.62323 g, 12.00 mmol, MW 386.36, Sigma-Aldrich) at room temperature. The resulting thick slurry was heated with an oil bath at 84° C. to a water white solution. After removal of the heat, the reaction was allowed to cool to 28° C. (bath temp.) and was seeded with S-ketamine L-(−)-DPPTA salt (from a previous preparation). After stirring at rt overnight, the flask was cooled with an ice bath and the white solids were filtered, washed with a small amount of ice-cold ethanol, dried under vacuum and transferred to a tared flask. The resulting white solid, 1A, 3.3381 g (Yield=89%) of the L-DPPTA salt of (S)-ketamine had a specific rotation [α]_(D)=−128° (c=1, T=21° C., DMF).

The filtrate was transferred to a round-bottom flask and concentrated in vacuo to a white solid. This was treated with 7.5 mL of acetonitrile and heated with a condenser and oil bath to 85° C. The resulting slurry was treated with a total of 6.7 mL of methanol. The resulting homogeneous solution was allowed to slowly stir while cooling to room temperature overnight, creating a white slurry which was further cooled in an ice bath. The solids were filtered, washed with a small amount of acetonitrile followed by a small amount of methyl tert-butyl ether. The solids were transferred to a tared flask and dried under vacuum to a white solid. The resulting white solid, 1B, 2.6313 g (yield=70%) of the (L)-DPPTA salt of (R)-ketamine had a specific rotation [α]_(D)=−28° (c=1, T=21° C., DMF).

Step 2: Preparation of the Free Base of S-(+)-Ketamine and R-(−)-Ketamine.

A mixture of 9.0769 g (14.5 mmol) of (S)-Ketamine salt 1B, 58.4 ml water and 63.5 mL toluene was stirred in a 250 mL round-bottom flask while adding 32 mL of 1N NaOH. After 20 min. the mixture was transferred to a separatory funnel, the organic layer was combined with 2×63 mL extractions of the aqueous layer. The organic layers were washed 2×50 mL water, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was azeotroped in vacuo with methanol and the remaining oil was treated with ethanol to precipitating a white solid. Removal of the remaining methanol in vacuo resulted in pure (S)-ketamine free base a s white granular solid, 1a, 3.2915 g, 95.46%.

[α]_(D) ^(22.3)° C.=−55°, in 2% ethanol,

Mass spectrum: [M+]=238

M.P.=120-121° C.

In the same manner, 2.5 g (4.01 mmol) of the (R)-Ketamine salt 1 b was converted to the free base 1 b as a white solid, 0.9452 g (99.3%),

[α]_(D) ^(22.3)° C.=−+54°, in 2% ethanol.

Example 2 Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine trihydrochloride (2a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine trihydrochloride (2b, Trans-)

A 50 mL round-bottom flask fitted with a water condenser and magnetic stir bar was charged with 0.5009 g (1.827 mmol) of S-(+)-ketamine hydrochloride 1a (Sigma-Aldrich, Inc) and 15 mL of absolute ethanol. While stirring, 0.7 mL (MW=128.2, d=1.014 g/ml) of 1-(3-aminopropyl)pyrrolidine (Tokyo Chemical Industry TCl America, Portland, Oreg.) was added, followed by 1.1 mL (MW=284.2, d=0.96 g/mL) of titanium (IV) isopropoxide (TCl America). The reactants were heated to reflux overnight. After 24 hr., an additional 0.54 mL of titanium (IV) isopropoxide was added and reflux was continued overnight. The reaction was then allowed to cool to room temperature at which point 138.2 mg of sodium borohydride in 8.0 mL of anhydrous ethanol was slowly added with stirring. The reaction was then treated with 13 mL of 1N HCl to a pH of 2.0. The resulting milky white slurry was transferred to a 250 mL round-bottom flask. Ethyl acetate (32 mL) was added and the pH readjusted to 10-11 with 1N NaOH (15 mL). This mixture was filtered through diatomaceous earth (d.e.), washing the cake with 2×10 mL EtOAc. The filtrate was transferred to a separatory funnel, 20 mL of saturated aqueous NaCl was added and the organic layer was isolated.

The organic layer was absorbed onto 2.6 g of silica gel 60A (Sigma-Aldrich Co.) and this was processed on a Teledyne-Isco CombiFlash Rf+ Lumen through a RediSep Rf High Performance Gold (40 gram, 40-60 micron silica) disposable flash column using 50% EtOAc: 50% IPO: 1.5-5.0% triethylamine as the mobile phase.

The less polar (LP) fractions 12-15 and the more polar (MP) fractions 18-22 were isolated and separately concentrated in vacuo.

The LP fractions produced 100.9 mg of colorless oil (trans-isomer). ¹H-NMR (400 MHz, CDCl₃) was consistent for the product. The oil was dissolved in EtOAc and treated with 3.3 equivalents of 2M HCl in Et₂O) (Sigma-Aldrich) with stirring to precipitate the HCl salt as a white solid, 2b, 0.1376 g. Mass spectrum calculated for C₁₃H₁₆ClNO: m/e 352, 350 ([M+H]+, 20%), 321, 319 (100%).

The MP fractions produced 258.6 mg of a colorless oil (cis-isomer). ¹H-NMR (400 MHz, CDCl₃) was consistent for the product. The oil was similarly dissolved in EtOAc and treated with 3.3 equivalents of 2M HCl in Et₂O to precipitate the HCl salt as a white solid, 2a, 0.2860 g. Mass spectrum calculated for C₁₃H₁₆ClFNO: m/e 352, 350 ([M+H]+, 100%), 321, 319 (20%).

Example 3 Cis-(1S,2S)-1-(2-chlorophenyl)-N²-[3-(4-fluorophenyl)propyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (3a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N²-[3-(4-fluorophenyl)propyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (3b, Trans-)

Using a similar procedure to that of Example 2, 89.5 mg of (S)-ketamine 1a and 100 mg of 3-(4-fluorophenyl)propylamine (Sigma-Aldrich Co) were converted to the corresponding cis- and trans-diastereomers, 3a and 3b as solid white dihydrochloride salts.

3a: 37.5 mg (61%). Mass spectrum calculated for C₂₂H₂₈ClFN₂: m/e 377, 375 ([M+H]+, 65%), 346, 344 (100%).

3b: 37.6 mg (61%). Mass spectrum calculated for C₂₂H₂₈ClFN₂: m/e 377, 375 ([M+H]+, 20%), 346, 344 (100%).

Example 4 Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-phenylpropyl)cyclohexane-1,2-diamine dihydrochloride (4a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-phenylpropyl)cyclohexane-1,2-diamine dihydrochloride (4b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and 0.31 mL of 3-phenyl-1-propylamine (Sigma-Aldrich Co) were converted to the corresponding cis- and trans-diastereomers, 4a and 4b as solid white dihydrochloride salts.

4a: 161.4 mg (69%). Mass spectrum calculated for C₂₂H₂₉ClN₂: m/e 359, 357 ([M+H]+, 100%), 328, 326 (80%).

4b: 81.4 mg (35%). Mass spectrum calculated for C₂₂H₂₉ClN₂: m/e 359, 357 ([M+H]+, 25%), 328, 326 (100%).

Example 5 Cis-(1S,2S)-1-(2-chlorophenyl)-N²-[3,4-dimethoxyphenethyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (5a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N²-[3,4-dimethoxyphenethyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (5b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and 3,4-dimethoxy-phenethylamine (TCl) were converted to the corresponding cis- and trans-diastereomers, 5a and 5b as solid white dihydrochloride salts.

5a: 123.3 mg (28%). Mass spectrum calculated for C₂₃H₃₁ClN₂O₂: m/e 405, 403 ([M+H]+, 60%), 374, 372 (100%).

5b: 106.3 mg (24.5%). Mass spectrum calculated for C₂₃H₃₁ClN₂O₂: m/e 405, 403 ([M+H]+, 10%), 374, 372 (100%).

Example 6 Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclohexane-1,2-diamine trihydrochloride (6a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclohexane-1,2-diamine trihydrochloride (6b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and 3-aminopropyl-morpholine (TCl) were converted to the corresponding cis- and trans-diastereomers, 6a and 6b as solid white trihydrochloride salts.

6a: 75.4 mg (21.7%). Mass spectrum calculated for C₂₀H₃₂ClN₃₀: m/e 368, 366 ([M+H]+, 100%), 337, 335 (20%).

6b: 124.9 mg (36%). Mass spectrum calculated for C₂₀H₃₂ClN₃₀: m/e 368, 366 ([M+H]+, 10%), 337, 335 (100%).

Example 7 Cis-(1R,2S)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride (7a, Cis-) Trans-(1R,2R)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride (7b, Trans-)

Using a similar procedure to that of Example 2, 300 mg of (R)-ketamine 1b and benzylamine (TCl) were converted to the corresponding cis- and trans-diastereomers, 7a and 7b as solid white dihydrochloride salts.

7a: 89.8 mg (35%). Mass spectrum calculated for C₂₀H₂₅ClN₂: m/e 331, 329 ([M+H]+, 5%), 300, 298 (100%).

7b: 46.3 mg (18%). Mass spectrum calculated for C₂₀H₂₅ClN₂: m/e 331, 329 ([M+H]+, 10%), 300, 298 (100%).

Example 8 Cis-(1S,2R)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride (8a, Cis-) Trans-(1S,2S)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride (8b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and benzylamine (TCl) were converted to the corresponding cis- and trans-diastereomers, 8a and 8b as solid white dihydrochloride salts.

8a: 58.3 mg (19.8%). Mass spectrum calculated for C₂₀H₂₅ClN₂: m/e 331, 329 ([M+H]+, 125%), 300, 298 (100%).

8b: 109.9 mg (38%). Mass spectrum calculated for C₂₀H₂₅ClN₂: m/e 331, 329 ([M+H]+, 10%), 300, 298 (100%).

Example 9

Cis-(1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidin-1-yl)propyl)-cyclohexane-1,2-diamine trihydrochloride (9a, Cis-)

Trans-(1R,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidin-1-yl)propyl)-cyclohexane-1,2-diamine trihydrochloride (9b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (R)-ketamine 1a and 3-(aminopropyl-pyrrolidine (TCl) were converted to the corresponding cis- and trans-diastereomers, 9a and 9b as solid white trihydrochloride salts.

9a: 165.3 mg (21.7%). Mass spectrum calculated for C₂₀H₃₂ClN₃: m/e 352, 350 ([M+H]+, 100%), 321, 319 (20%).

9b: 35 mg (6%). Mass spectrum calculated for C₂₀H₃₂ClN₃: m/e 352, 350 ([M+H]+, 45%), 321, 319 (100%).

Example 10 Cis-(1R,2S)-1-(2-chlorophenyl)-N²-[3,4-dimethoxyphenethyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (10a, Cis-) Trans-(1R,2R)-1-(2-chlorophenyl)-N²-[3,4-dimethoxyphenethyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (10b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (R)-ketamine 1a and homoveratrylamine (TCl) were converted to the corresponding cis- and trans-diastereomers, 10a and 10b as solid white dihydrochloride salts.

10a: 58.2 mg (21%). Mass spectrum calculated for C₂₃H₃₁ClN₂O₂: m/e 405, 403 ([M+H]+, 35%), 374, 372 (100%).

10b: 33.9 mg (12%). Mass spectrum calculated for C₂₃H₃₁ClN₂₀₂: m/e 405, 403 ([M+H]+, 8%), 374, 372 (100%).

Example 11 Cis-(1S,2S)-1-(2-chlorophenyl)-N²-[3,4-dichlorobenzyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (11a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N²-[3,4-dichlorobenzyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride (11b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and 3,4-dichlorobenzylamine (TCl) were converted to the corresponding cis- and trans-diastereomers, 11a and 11 b as solid white dihydrochloride salts.

11a: 26.3 mg (6%). Mass spectrum calculated for C₂₀H₂₃C₁₃N₂: m/e 401, 399, 397 ([M+H]+, 7%), 370, 368, 366 (100%).

11b: 51.4 mg (12%). Mass spectrum calculated for C₂₀H₂₃ClN₂: m/e 401, 399, 397 ([M+H]+, 5%), 370, 368, 366 (100%).

Example 12 Cis-(1S,2S)—N²-(3-aminopropyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine trihydrochloride (12a, Cis-) Trans-(1S,2R)—N²-(3-aminopropyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine trihydrochloride (12b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and 1,3-diaminopropane (TCl) were converted to the corresponding cis- and trans-diastereomers, 12a and 12b as solid white trihydrochloride salts.

12a: 81.7 mg (27%). Mass spectrum calculated for C₁₆H₂₆ClN₃: m/e 298, 296 ([M+H]+, 10%), 267, 265 (100%).

12b: 62.9 mg (21%). Mass spectrum calculated for C₁₆H₂₆ClN₃: m/e 298, 296 ([M+H]+, 45%), 267, 265 (100%).

Example 13 Cis-(1S,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)cyclohexane-1,2-diamine tetrahydrochloride (13a, Cis-) Trans-(1S,2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)cyclohexane-1,2-diamine tetrahydrochloride (13b, Trans-)

Using a similar procedure to that of Example 2, 300 mg (1.094 mmol) of (S)-ketamine 1a and 3-(4-methylpiperazin-1-yl)propan-1-amine (Combi-Blocks, Inc., San Diego, Calif.) were converted to the corresponding cis- and trans-diastereomers, 13a and 13b as solid white tetrahydrochloride salts.

13a: 267 mg (76%). Mass spectrum calculated for C₂₁H₃₅ClN₄: m/e 381, 379 ([M+H]+, 100%), 350, 348 (15%).

13b: 121.4 mg (35%). Mass spectrum calculated for C₂₁H₃₅ClN₄: m/e 381, 379 ([M+H]+, 35%), 350, 348 (100%).

Determination of Pharmacological Activity

The compounds from the above Examples were tested for Sigma-1 and Sigma-2 activity. Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program (PDSP), Contract #HHSN-272-2013-000017-C(NIMH-PDSP). The NIMH-PDSP is directed by Bryan L Roth MD, PhD at the University of North Carolina at Chapel Hill, N.C. and Project Officer Jamie Driscoll at NIMH, Bethesda, Md., USA. Procedures employed by the PDSP as described in the NIMH-PDSP Assay Protocol Book, Version II. The standard drug used in both Sigma subtype assays is haloperidol.

DATA

Sigma-1, Sigma-2, Example Ki (nM) Ki, (nM)  2a 17.3 59.8  2b 37.2 305  3a 35.4 18  3b 216.7 675  4a 97.2 15.5  4b 697 425.7 13a 70 98 13b 146 435 

The invention claimed is:
 1. A method of treatment of a disorder or condition in a mammal, selected from the group consisting of chronic cancer pain, pain from post-traumatic nerve damage, diabetic neuropathy pain, chronic primary pain, fibromyalgia, post-surgical pain, chronic visceral pain, chronic headache, pain from orofacial disorders, pain from musculoskeletal disorders, spinal cord injury pain, inflammatory pain and musculoskeletal pain, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X and Y are independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, CF₃, C₂F₅, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₃-alkoxy, aryl, heteroaryl, -(—C═O)—R5, —NH—(C═O)—R5, —NR5-(C═O)—R6, —(C═O)—NHR5 and —(C═O)—NR5R6; R1 is hydrogen; R2 is hydrogen or C₁-C₆-alkyl; R3 is hydrogen or C₁-C₆-alkyl; R4 is selected from the group consisting of C₁-C₆-alkyl, C₃-C₇-cycloalkyl and (CH₂)_(n)—R7, or NR3R4 is a 5- to 12-membered cyclic or bicyclic ring system containing up to two additional heteroatoms in the ring, selected from N, O and S; R5 is selected from C₁-C₆-alkyl and aryl; R6 is selected from C₁-C₆-alkyl and aryl; or NR5R6 is a 5- to 12-membered cyclic or bicyclic ring system containing up to two additional heteroatoms in the ring, selected from N, O and S; R7 is independently selected from the group consisting of H, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, (C₁-C₆-alkyloxy)-, (C₁-C₆-alkyloxy)-(C₁-C₆-alkyl)-, NR8R9-, NR8R9-(C₁-C₆-alkyl), -aryl, heterocyclyl and heteroaryl; R8 and R9 are independently selected from hydrogen, C₁-C₆-alkyl and aryl, or taken together with the N atom to which they are attached form a 3- to 8-membered ring containing up to two additional heteroatoms, selected from N, O and S; “a”, “b” are chiral carbon atoms; and n is an integer between 0 and
 6. 2. The method of claim 1 wherein R4 is C₁-C₆-alkyl, C₃-C₇-cycloalkyl or (CH₂)_(n)—R7 and wherein n is an integer between 0 and
 6. 3. The method of claim 1 wherein R7 is selected from the group consisting of H, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, (C₁-C₆-alkyloxy)-(C₁-C₆-alkyl)-, NR8R9-(C₁-C₆-alkyl)-, aryl, heterocyclyl and heteroaryl.
 4. The method of claim 1 wherein said compound is selected from: Cis-(1S, 2S)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine trihydrochloride; Trans-(1S, 2R)-1-(2-chlorophenyl)-N¹-methyl-N²-[3-(pyrrolidin-1-yl)propyl]-cyclohexane-1,2-diamine trihydrochloride; Cis-(1S, 2S)-1-(2-chlorophenyl)-N²-[3-(4-fluorophenyl)propyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride; Trans-(1S, 2R)-1-(2-chlorophenyl)-N²-[3-(4-fluorophenyl)propyl]-N¹-methyl-cyclohexane-1,2-diamine dihydrochloride; Cis-(1S, 2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-phenylpropyl)cyclohexane-1,2-diamine dihydrochloride; Trans-(1S, 2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-phenylpropyl)cyclohexane-1,2-diamine dihydrochloride; Cis-(1S, 2S)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl]-N¹-methylcyclo-hexane-1,2-diamine dihydrochloride; Trans-(1S, 2R)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl]-N¹-methylcyclo-hexane-1,2-diamine dihydrochloride; Cis-(1S, 2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclohexane-1,2-diamine trihydrochloride; Trans-(1S, 2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(morpholinopropyl)cyclo-hexane-1,2-diamine trihydrochloride; Cis-(1R, 2S)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride; Trans-(1R, 2R)—N²-benzyl-1-(2-chlorophenyl-N¹-methylcyclohexane-1,2-diamine dihydrochloride; Cis-(1S, 2R)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride; Trans-(1S, 2S)—N²-benzyl-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride; Cis-(1R, 2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidin-1-yl)propyl)cyclo-hexane-1,2-diamine trihydrochloride; Trans-(1R, 2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidin-1-yl)propyl)cyclo-hexane-1,2-diamine trihydrochloride; Cis-(1R, 2S)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl]-N¹-methylcyclo-hexane-1,2-diamine dihydrochloride; Trans-(1R, 2R)-1-(2-chlorophenyl)-N²-(3,4-dimethoxyphenethyl]-N¹-methylcyclo-hexane-1,2-diamine dihydrochloride; Cis-(1S, 2S)-1-(2-chlorophenyl)-N²-(3,4-dichlorobenzyl)-N¹-methylcyclohexane-1,2-diamine dihydrochloride; Trans-(1S, 2R)-1-(2-chlorophenyl)-N²-(3,4-dichlorobenzyl)-N¹-methylcyclo-hexane-1,2-diamine dihydrochloride; Cis-(1S, 2S)—N²-(3-aminopropyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine trihydrochloride; Trans-(1S, 2R)—N²-(3-aminopropyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine trihydrochloride; (1S, 2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)-cyclohexane-1,2-diamine tetrahydrochloride; and (1S, 2R)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)-cyclohexane-1,2-diamine tetrahydrochloride.
 5. The method of claim 1 wherein said compound is selected from: (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidine-1-yl)propyl)cyclohexane-1,2-diamine; (1R,2S)—N²-(3-(1H-pyrrol-1-yl)propyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(2-methyl-1H-imidazol-1-yl)propyl)-cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(4-methylpiperazin-1-yl)propyl)cyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-morpholinopropyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-(pyrrolidine-1-yl)propyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(3-(dimethylamino)propyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(3,4-dimethylbenzyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)—N²-(1-chlorobenzyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-(2-chlorophenyl)-N²-(3,5-difluorobenyl)-N¹-methylcyclohexane-1,2-diamine; (1R,S2)-1-(2-chlorophenyl)-N¹-methyl-N²-(4-(trifluoromethyl)benzyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(4-((trifluoromethyl)thio)benzyl)cyclo-hexane-1,2-diamine; (1R,2S)—N²-(5-chloro-2-fluorobenzyl)-1-(2-chlorophenyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(5-methoxy-2-methylbenzyl)-N¹-methylcyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(thiazol-2-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(thiophen-3-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(furan-2-ylmethyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(thiophen-2-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-((1-methyl-1H-pyrazol-4-yl)methyl)-cyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(cyclobutylmethyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(cyclopropylmethyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-neopentylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(2,2-difluoroethyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(cyclopropylethyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²-(cyclohexylmethyl)-N¹-methylcyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-quinuclidin-3-yl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-quinuclidin-3-yl)cyclohexane-1,2-diamine (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyridin-4-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyridin-2-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyrimidin-2-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(3-methylpyridin-4-yl)methyl)cyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(pyrazin-2-ylmethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-(quinoline-6-ylmethyl)cyclohexane-1,2-diamine (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²-((1-methyl-1H-indol-5-yl)methyl)cyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²—((S)-1-(4-methoxyphenyl)ethyl)-N¹-methylcyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N²—((R)-1-(4-methoxyphenyl)ethyl)-N¹-methylcyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-1-phenylethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-1-phenylethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-1-(p-tolyl)ethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-1-(p-tolyl)ethyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)cyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-1,2,3,4-tetrahydronaphthalen-1-yl)cyclo-hexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((R)-2-phenylpropyl)cyclohexane-1,2-diamine; (1R,2S)-1-(2-chlorophenyl)-N¹-methyl-N²—((S)-2-phenylpropyl)cyclohexane-1,2-diamine; (R)-1-((1S,2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexyl)-N,N-dimethyl-pyrrolidin-3-amine; and (S)-1-((1S,2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexyl)-N,N-dimethyl-pyrrolidin-3-amine.
 6. The method of claim 1 wherein said mammal is a human.
 7. The method of claim 1 wherein a compound of the formula (I) and pregabalin are co-administered to a mammal in need of such treatment.
 8. The method of claim 7 wherein the mammal is a human.
 9. The method of claim 1 wherein a compound of the formula (I) and gabapentin are co-administered to a mammal in need of such treatment.
 10. The method of claim 9 wherein the mammal is a human. 